In-hospital mortality risk stratification of Asian ACS patients with artificial intelligence algorithm

Background Conventional risk score for predicting in-hospital mortality following Acute Coronary Syndrome (ACS) is not catered for Asian patients and requires different types of scoring algorithms for STEMI and NSTEMI patients. Objective To derive a single algorithm using deep learning and machine learning for the prediction and identification of factors associated with in-hospital mortality in Asian patients with ACS and to compare performance to a conventional risk score. Methods The Malaysian National Cardiovascular Disease Database (NCVD) registry, is a multi-ethnic, heterogeneous database spanning from 2006–2017. It was used for in-hospital mortality model development with 54 variables considered for patients with STEMI and Non-STEMI (NSTEMI). Mortality prediction was analyzed using feature selection methods with machine learning algorithms. Deep learning algorithm using features selected from machine learning was compared to Thrombolysis in Myocardial Infarction (TIMI) score. Results A total of 68528 patients were included in the analysis. Deep learning models constructed using all features and selected features from machine learning resulted in higher performance than machine learning and TIMI risk score (p < 0.0001 for all). The best model in this study is the combination of features selected from the SVM algorithm with a deep learning classifier. The DL (SVM selected var) algorithm demonstrated the highest predictive performance with the least number of predictors (14 predictors) for in-hospital prediction of STEMI patients (AUC = 0.96, 95% CI: 0.95–0.96). In NSTEMI in-hospital prediction, DL (RF selected var) (AUC = 0.96, 95% CI: 0.95–0.96, reported slightly higher AUC compared to DL (SVM selected var) (AUC = 0.95, 95% CI: 0.94–0.95). There was no significant difference between DL (SVM selected var) algorithm and DL (RF selected var) algorithm (p = 0.5). When compared to the DL (SVM selected var) model, the TIMI score underestimates patients’ risk of mortality. TIMI risk score correctly identified 13.08% of the high-risk patient’s non-survival vs 24.7% for the DL model and 4.65% vs 19.7% of the high-risk patient’s non-survival for NSTEMI. Age, heart rate, Killip class, cardiac catheterization, oral hypoglycemia use and antiarrhythmic agent were found to be common predictors of in-hospital mortality across all ML feature selection models in this study. The final algorithm was converted into an online tool with a database for continuous data archiving for prospective validation. Conclusions ACS patients were better classified using a combination of machine learning and deep learning in a multi-ethnic Asian population when compared to TIMI scoring. Machine learning enables the identification of distinct factors in individual Asian populations to improve mortality prediction. Continuous testing and validation will allow for better risk stratification in the future, potentially altering management and outcomes.


Objective
To derive a single algorithm using deep learning and machine learning for the prediction and identification of factors associated with in-hospital mortality in Asian patients with ACS and to compare performance to a conventional risk score.

Methods
The Malaysian National Cardiovascular Disease Database (NCVD) registry, is a multi-ethnic, heterogeneous database spanning from 2006-2017. It was used for in-hospital mortality model development with 54 variables considered for patients with STEMI and Non-STEMI (NSTEMI). Mortality prediction was analyzed using feature selection methods with machine learning algorithms. Deep learning algorithm using features selected from machine learning was compared to Thrombolysis in Myocardial Infarction (TIMI) score.

Introduction
Acute coronary syndrome (ACS), also known as a heart attack, is a leading cause of death and disability in the Asian region, with an in-hospital mortality rate of more than 5% [1]. Coronary artery disease (CAD) is responsible for 20-25% of deaths in public hospitals in South-East Asia [2,3] and frequently manifest as ACS. The three clinical manifestations of ACS are STEMI, non-STEMI, and unstable angina (UA) [4,5].
In ACS patients, Thrombolysis in Myocardial Infarction (TIMI) and the Global Registry of Acute Coronary Events (GRACE) [6] used in clinical guidelines to predict mortality risk. The TIMI STEMI Risk score is only for STEMI patients; NSTEMI patients require a different TIMI score, NSTEMI. GRACE is applicable in both scenarios. Big data techniques could provide additional insight because TIMI and GRACE only cover traditional prognostic factors [7]. The requirement to wait for blood results measuring renal function restricts the use of the GRACE risk score in practice and delays prediction.
The TIMI and GRACE risk scores were calculated using data from a Western Caucasian cohort with limited participation from an Asian cohort. Asian patients have been understudied [8], and Asians are more likely to develop ACS, diabetes, hypertension, and chronic kidney disease at a younger age and seek medical attention later [8][9][10]. The bi-annual NCVD ACS Registry, which is publicly available online, publishes evidence of a higher prevalence of risk factors as well as earlier onset of heart disease [11]. Similar findings are seen in registry data from Korea (KAMIR registry), Singapore (SAMIR), and the Gulf countries. This is in reference to well-published data derived primarily from Western literature and utilizing Caucasians in their database [12].
A model that can better predict ACS patient mortality will improve prognosis. A mortality risk scoring system based on machine learning (ML) and deep learning (DL) algorithms reduces information loss from conventional risk scores [13].
These algorithms have been found to be useful in calculating mortality risk in our previous study in patients with STEMI [14][15][16]. Similar studies in Korean and Chinese only population have also been reported [17][18][19].
Different ML algorithms and features chosen from these ML algorithms on population-specific datasets enables the identification of distinct factors for improved mortality prediction over TIMI [20,[26][27][28]. Because different algorithms result in different features being selected, it is possible to compare which algorithm and combination of features will produce better results than the TIMI risk score.
When compared to traditional ML algorithms, DL outperformed in terms of in-hospital mortality post ACS, reducing the need for feature engineering and extraction [7,29,30]. DL algorithms automatically learn features and classify data better than conventional ML [31,32]. To improve model performance, ML algorithms require feature selection methods [33]. Unlike ML algorithms, the interpretation of the important variables for the decision of the risk scores is unknown in DL models [7].
Identifying risk factors for mortality improves clinical patient care. To better understand DL's "black box" feature selection, we incorporate ML features into the DL model as in Kasim's research [34].We anticipate that integrating DL and ML feature selection algorithms can improve model accuracy and understanding of factors associated with in-hospital mortality prediction in Asian ACS patients. Additionally, we intend to compare the performance of ML with that of DL developed utilising both complete and selected features from the ML feature selection algorithm. We also aim to verify the developed ML and DL prediction models against the TIMI risk score, utilizing multi-ethnic registry data on Asian ACS patients.

Study data
We used data from Malaysian National Cardiovascular Database (NCVD-ACS) registries from 2006 to 2017 from ten participating hospitals. The NCVD registry was approved by the Malaysian Ministry of Health (MOH) in 2007. (Approval Code: NMRR-07-20-250). It waived NCVD informed patient consent and the patient information was anonymize to be use in our study. In addition to outcomes, the registry collects data on a predefined set of clinical, demographic and procedural factors from participants [20,25,35]. The UITM ethics committee (Reference number: 600-TNCPI (5/1/6)) and the National Heart Association of Malaysia (NHAM) authorised the study with the approval code REC/673/19. The UiTM Ethics Committee operates in accordance to the ICH Good Clinical Practice Guidelines, Malaysia Good Clinical Practice Guidelines and Declaration of Helsinki.
All patients from the ACS registry without exclusion were used including patients who received reperfusion (fibrinolysis, primary PCI (PPCI), angiography demonstrating spontaneous reperfusion, or urgent coronary artery bypass grafting (CABG)). In this context, STEMI was defined as persistent ST-segment elevation �1mm in two contiguous electrocardiographic leads, or the presence of a new left bundle branch block in the setting of positive cardiac markers. NSTEMI is defined by the presence of acute chest pain with positive cardiac markers but without persistent ST-segment elevation [36].
This study examined 54 variables drawn from a comprehensive set of data derived from clinical guidelines. Sociodemographic characteristics, CVD diagnosis and severity, CVD risk factors, CVD comorbidities, non-CVD comorbidities, biomarkers, and medication use were all included in the variables. In-hospital mortality was calculated from the time of initial hospitalization. The Malaysian National Registration Department confirms fatalities on an annual basis. The registry's data excludes short-term complications such as heart failure. The study discarded follow-up data points due to an excessive number of missing values. To maximize the study's impact, we focused our algorithm on potentially policy-changing outcomes that is mortality. Several more publications make a similar point [7,20,37].
Classification and sample pre-processing Complete cases. We used a complete set of data to ensure the validity of the findings for model development for the primary analysis. A total of 68,528 ACS cases from the registry were collected and 13,190 were identified as complete cases (with no missing values on predictors). This rendered complete cases of patients with a full predictor set of 54 variables (10 continuous, 44 categorical).
Missing cases. Secondary analyses on the best performing algorithm were carried out on the 68,528 ACS cases that includes missing cases. Our imputation dataset model was based on Wallert et al. study [38]. In the study, two different models were developed for training and testing using both complete and imputed cases. Comparing the performance of both models revealed that imputed analyses produced comparable results to the full case model.
We used two imputation approaches from R package missForest [39] and multivariable imputation using predictive mean matching [40].
Our definition of an incomplete dataset includes missing variables of up to 30 percent. There are no missing data for electrocardiography, age, or gender; however, there are fewer than 15% missing data for race (3%), pharmaceutical therapy (2%-14%), invasive therapeutic procedures (less than 8%), clinical representation (less than 3%) and status before ACS occurrence (5%-15%). Up to 30% of the data for baseline intervention variables and Killip class is missing.
The missing dataset referenced is for patient characteristics, not outcomes. Due to the prospective structure of our dataset and the retroactive administration of data, the proportion of missing values across all variables was completely unpredictable and beyond our control. The probability of missing values in our dataset is independent of both the observed values in any variable and the unseen portion of the dataset.
Consequently, the dataset is categorized as missing completely at random (MCAR), which suggests that the pattern of missing values is independent of any variable that may or may not be included in the study. Table 1 shows the baseline characteristics for complete set and imputed dataset.
Data splitting. We used stratified random sampling of data [41]. Data were split for model development (70%) and validation (30%) for complete and missing cases which are shown in Fig 1 below. We accessed the performance of the developed model and TIMI using a validation set that accounts for 30% of data that was not used for model development. Fig 1  below shows the details of the study data. Data normalization. Data normalization is a pre-processing step where data is scaled or altered to contribute equally to each feature. This reduces the bias of features that contribute more numerically to pattern class discrimination [42].
We employed standardization or z-score normalization, where values are centred around the mean with a unit standard deviation, resulting in a mean of zero with a unit standard deviation.
Using z-score normalization, continuous variables (age, heart rate, Systolic and Diastolic Blood Pressure, Peak CK, Total Cholesterol, HDL, LDL, Triglyceride, Fasting Blood Glucose were normalized. Algorithm development and calibration. We used DL and ML classification methods, random forest (RF), support vector machine (SVM), and logistic regression (LR). They are the classifiers that outperform traditional approaches in mortality studies [20,43]. K-fold cross validation was used to during the algorithm training the value of k was set to k = 5. Each algorithm was trained with all 54 variables and features obtained by sequential backward elimination features selection (SBE).
The DL and ML algorithms' parameters were tuned for better prediction as referred to Table 1. Tuned hyperparameters are known to outperform the default settings in ML and DL models [44].
The area under the curve (AUC) was used to assess predictive performance [45]. Model calibration performance indicators were accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) [46]. In addition, we used McNemar's test, a nonparametric approach for testing row and column marginal frequencies [47].
The McNemar test can also be used to compare two groups on a dichotomous dependent variable. In contrast to independent data, McNemar's test uses dependent (paired or correlated) data [48]. In addition, the paired resampled t-test was performed [41,49]. Table 2 shows the hyperparameters used in ML Models Development as for Table 3 displays the hyperparameters used for all the DL models with all and selected features. Feature selection. By removing duplicate, irrelevant, or noisy features from the original set of features, feature selection reduces dimensionality and improves learning performance [50].
Using classifier specific variable evaluators, we employed feature selection to rank variables. The relevance of variables related to outcome (in-hospital survival) was ranked using RF, SVM, and LR.
Then, sequential backward elimination (SBE) [51] was performed to reduce the number of features on the ML variables ranked in ascending order of relevance. Every time a variable is eliminated, the model is retrained and tested. The feature selection technique identifies the variable that reduces the AUC of the prediction model by a significant amount upon elimination. Next, we rank the selected variables again and resume the elimination procedure until we achieve a model with the least number of variables and the highest AUC. The DL algorithm was then trained using the final set of ML feature variables.
Shapley Additive Explanations (SHAP) were used to interpret our model because Shapley values are used to measure the contribution of input features to the output of a machine learning model at the instance level. These SHAP values encode the importance that a model assigns to a feature, so we can use them to order the features according to their importance [52]. A SHAP force plot was also used to show how features influenced the model's prediction for a specific observation. This explains how the model came to make the prediction it did for a specific observation [53]. Comparison with TIMI score. Performance was compared using NCVD registry calculated STEMI and NSTEMI TIMI scores. The AUC of the TIMI score was compared to the developed DL and ML-based models using the 30% validation set. Based on clinical and research cut off points, we created a graph to compare the best model and TIMI score [54]. A high risk of death was defined as a probability risk of death greater than 8%, as defined by Correia et al. [54].
The best model and TIMI risk scores were compared using net reclassification improvement (NRI). The NRI employs reclassification tables to analyse whether reclassifying patients using a different technique to mortality assessment adds value. The NRI allowed us to quantify how well the various mortality risk assessment methods drove correct category change. An NRI is the percentage improvement in net categorization employing a new approach. The NRI was calculated by comparing the TIMI risk score for STEMI and NSTEMI to the best model for STEMI and NSTEMI [55]. Additional statistics. The findings are provided as mean + SD, and categorical variables as frequency and percentage. We used correlation analysis to find a substantial association between variables. We used a Chi-Square test to identify significant variables and a two-sided independent student t-test (p = 0.05) to compare them. The t-test was used to compare the performance of all develop models [56,57]. Statistical significance was defined as 0.05 or less.
Software. R package (Version 3.5.2) was used in DL and ML algorithm development. Statistical analysis was conducted using Statistical Package for Social Sciences (SPSS) program version 16.0 [58].

Patient characteristics
A total of 68,528 ACS patients were identified. After removing patients with incomplete data, 68,528 patients were enrolled. Table 2 illustrates patients' characteristics used in this study on the complete dataset and imputed dataset. The mean age was 58.42 (SD = 12.04). The majority of patients (~79.7%) were males. The overall mortality reported for in-hospital was 5.41%. STEMI patients (58.70%) and NSTEMI patients (41.30%) excluding the unstable angina patients (UA), made the complete case population dataset and for imputed dataset STEMI patients comprised of 46.91% and NSTEMI, 53.09%. There were significant differences between survivors to non-survivors for in-hospital, in terms of age, gender, smoking status, history of diabetes, hypertension, family history of premature cardiovascular disease, heart failure, renal disease, heart rate, history of cerebrovascular disease, heart rate, systolic blood pressure, diastolic blood pressure, Killip class, total cholesterol, LDL, triglyceride, fasting blood glucose, ECG abnormalities, cardiac catheterization, PCI, anterior leads, ASA, beta-blocker, ACE inhibitor, Angiotensin II Receptor Blocker, statin, diuretics, insulin, calcium antagonist, oral hypoglycemia and anti-arrhythmic agent use (p < 0.0001 for all). Both statistical analyses on the complete and imputed dataset are noted be almost similar.
Maximal predictive performances on the 30% testing dataset were observed for the models constructed using complete sets (54 variables) and a reduced set of variables compared to the TIMI risk score as shown in Table 4. All the DL and ML models outperformed TIMI risk scores in both STEMI and NSTEMI prediction which depicts in Fig 3. The best-selected model was DL (SVM selected var) (p<0.0001). Detailed performance evaluation of the DL and ML model against the TIMI risk score is presented in Table 5.

Performances evaluation
DL and ML algorithms constructed using all and selected features outperformed TIMI risk scores for both STEMI and NSTEMI predictions on the 30% untouched validation dataset (p < 0.0001).
The DL (SVM selected var) algorithm demonstrated the highest predictive performance with the least number of predictors (14 predictors) for in-hospital prediction of STEMI patients (AUC = 0.96, 95% CI: 0.95-0.96). In NSTEMI in hospital prediction, DL (all) without Table 4. The AUC of TIMI risk score, DL and ML models with and without feature selection based on a 30% validation dataset.

Models
The

Results of data imputation
Secondary analysis was conducted on the best performing algorithm with the least number of predictors DL (SVM selected var). The DL (SVM selected var) algorithm was trained and tested on the imputed dataset using two different imputation methods, MissForest and pmm are shown in Table 6. The DL (SVM selected var) on complete cases performed slightly better than the imputed model for STEMI and NSTEMI patients (p<0.0001). Similar performance was reported on the imputed dataset using both methods (p<0.0001).

Feature selection
SBE feature selection methods were combined with ML algorithms to construct predictive models with optimal performance (refer to methods). Table 7 illustrates final predictors ranked in ascending order of importance. Common predictors observed for in-hospital, across all ML feature selection models in this study are age, heart rate, Killip Class, cardiac catheterization, oral hypoglycaemic agents and antiarrhythmic agent. The best model DL (SVM selected var) were constructed using 14 features selected from SVM (varImp-SBE-SVM)  (Table 7). Common features between TIMI risk score for STEMI and NSTEMI and the features from the best model are age, heart rate, Killip Class, fasting blood sugar and angina. Fig 4 depicts the SHAP summary plot of the SVM (varImp-SBE-SVM) predictors that were combined with DL to achieve the highest performance accuracy.
The y-axis indicates the variable name in descending order of importance, with Killip class having the highest importance. On the x-axis is the SHAP value. The gradient colour indicates the variable's initial value. In Booleans, it can contain only two colours, but in numbers, it can contain the entire colour spectrum. Each point corresponds to a row in the initial dataset.
Having a high Killip class, heart rate, age, and fasting blood glucose is associated with high and negative values on the outcome, as observed. Where high is determined by the colour and negative by the x-value.
In other words, as the Killip class, age, fasting blood glucose (FBG), and heart rate increase, so does the mortality rate. Meanwhile, cardiac catheterization and medications like oral hypoglycemic agents, as well as high HDL levels, are linked to survival or a favorable outcome. In the acute setting, such as ACS, LDL-C appears to have a more neutral effect, with high values contributing to similar outcomes.
The SHAP force plot in Fig 5 illustrate explanation of the DL for one single observation. The binary goal is either survival (survival = 1) or non-survival (non-survival = 0). The bold  value 0.77 in the plot above represents the model's score for this observation. Higher scores cause the model to predict 1, while lower scores cause it to predict 0. The features that were important in making the prediction for this observation are shown in red and blue, with red representing features that increased the model score and blue representing features that decreased it. Features that had a greater impact on the score are located closer to the red-blue dividing line, and the size of that impact is represented by the size of the bar. As can be seen, the patient Killip class, age at onset of ACS, history of taking statins, and LDL Cholesterol values have a stronger association with a poorer outcome, i.e. death, which is similar to what is seen using traditional risk prediction methods. What's interesting is that variables like whether the patient had an in-patient cardiac catheterization, an abnormal ECG on admission, a history of diabetes and taking oral hypoglycemics, as well as high HDL cholesterol and fasting blood sugar, all help improve the algorithm's prediction of events, resulting in a better AUC with our algorithm.
The best model DL (SVM selected var) was converted into an in-hospital ACS online mortality calculator available at http://myheartstemiacs.uitm.edu.my/home.

Comparison of best model DL (SVM selected var) to TIMI risk score when applied to the validation dataset
Figs 6 and 7 illustrate the comparison of the best DL (SVM selected var) model mortality rate against the TIMI score for STEMI and NSTEMI. TIMI Risk Score for STEMI has a scale of 0-14 while TIMI Risk Score for NSTEMI has a scale of 0-7. We categorized DL score patients as low risk with the probability <50% and high-risk stratum as �50%. This is equivalent to TIMI low risk of score �5 and a high-risk score of > 5 for both STEMI and NSTEMI risk scores (5) (4).
The TIMI risk scores for STEMI correctly predicted 13.08% of the high-risk patient's STEMI death, whereas the TIMI risk scores for NSTEMI only predicted 4.65% of the high-risk patient's NSTEMI death (illustrates in Fig 4). In both STEMI and NSTEMI cases, the prediction using TIMI risk scores shows a poor prediction for the mortality rate of high-risk patients. The STEMI prediction model depicts an increasing trend, whereas the NSTEMI prediction model depicts a fluctuating trend.
Meanwhile, Fig 6 demonstrates the percentage of mortalities estimated at various probabilities using DL (SVM selected var) as the predictive model on the validation dataset.
The DL (SVM selected var) model correctly classified 24.87% of STEMI patients and 19.71% of NSTEMI patients as high risk (risk probabilities greater than 50%). When compared to the TIMI risk score, the DL (SVM selected var) classified a higher percentage of STEMI and NSTEMI high-risk patients.

Net Reclassification Index (NRI)
NRI for the in-hospital model, the net reclassification of STEMI patients using the DL (SVM selected var) is shown in Table 8. DL produced a net reclassification improvement of 18.14% with p<0.00001 over the original TIMI risk score. NRI for NSTEMI (Table 9) reported the net reclassification of patients improved using the DL (SVM selected var) produced a net reclassification improvement of 55.80% with p<0.00001 over the original TIMI risk score.

Discussions
Our study is the first to demonstrate improved in-hospital mortality prediction in a multi-ethnic Asian patient with ACS that used a combination of DL and ML feature selection methods.
On validation datasets, we demonstrated high performance for DL models using a combination of feature selection and ML classifier algorithms. Overall, the DL model, both with and without feature selection, outperformed the ML and TIMI risk scores for STEMI and NSTEMI in-hospital mortality. The best model identified in this study is the combination DL (SVM selected var) using 14 predictors with AUC of (STEMI = 0.96, NSTEMI = 0.95) for in-hospital ACS mortality prediction that resulted in better performance compared to other combinations of DL with ML and TIMI scoring as well. DL has proven to be better to ML in mortality studies using datasets of smaller or equal size to our study, achieving a higher AUC [7,25,59]. Conventional risk scoring such as TIMI uses logistic regression with few predictive parameters. The logistic regression model has two flaws: fixed assumptions on data behavior and the requirement to pre-select predictors during model development [7,11,60,61].
On the study dataset, combining features selected by the SVM algorithm with a DL classifier produced high performance to other ML algorithms selected features. Similar publications have been published demonstrating that the SVM algorithm with features selection outperformed other ML algorithms [38] and when utilizing similar population datasets as demonstrated in our study [28,62].
The TIMI score's simplicity is recognized in current guidelines and is frequently used in Asian hospitals for risk assessment of patients with ACS. The TIMI risk score, originally established to predict 30-day mortality, is used in Asian hospitals to predict in-hospital, 30-day, and 1-year mortality post ACS [39,[63][64][65]. Correia et al. reported that the TIMI score is better than GRACE score calibration because it has more variables associated with mortality, a balanced distribution of low, intermediate, and high-risk patients, and more accurate estimation [56]. However, the TIMI score has several notable limitations. First, TIMI was developed using data from fibrinolytic-eligible patients with STEMI where reperfusion therapy and drug-eluting stents were not regular treatments [66]. Statins and antiplatelet medicines like prasugrel and ticagrelor are now part of our everyday routine. Because TIMI risk scores only reflect the key prognostic indicators, valuable information may be missed [7]. Exclusion of the high-risk patients is also another limitation of the risk score [33]. The TIMI risk score lacks risk factors relevant to older adults and fails to account for the overall complexity of the older adult with ACS. The Asian cohort was found to be carrying an overall higher disease burden and risk compared to the TIMI cohort.
The lack of weighting for the risk factors, while improving usability, decreased TIMI risk score discriminatory performance [6,67]. In addition, there are different scoring systems for STEMI and NSTEMI.
To determine predictive mortality for ACS patients is important to strategize treatment plan and to improve outcomes. The database used for this study is unique in that it includes the three major ethnicities in Asia: Chinese, Indian, and Malay. Previous research relied on a homogeneous population database, raising concerns about its applicability to the Asian continent. The risk stratification model used in this study was developed using relatively recent data on Asian ACS patients, and it can better predict ACS patient mortality in modern practice. Different algorithms for the scoring method are eliminated for the status of the ST segment; moreover, the developed algorithm in our study can predict the mortality of ACS regardless of ST elevation. Despite the fact that the TIMI risk score is widely used in the Asian population, it was developed using data from a Western Caucasian cohort with limited data from an Asian population. A previous validation study in the Asian population reported a modest accuracy for risk prediction for TIMI risk score in STEMI with an AUC of 0.78 [68]. Other conventional risk scores also performed modestly when validated in Korean registry study for STEMI and NSTEMI patients using AUC as a performance metric GRACE (0.851 0.810), ACTION (0.852, 0.806) and TIMI score (0.781, 0.593). In this study TIMI score validation for STEMI and NSTEMI resulted in (0.83, 0.55), implying similar performance for predicting the mortality of ACS patients in the Asian region.
As a result, risk scoring tools should be tailored to a specific population to more accurately reflect differences. In this study, we found that TIMI underestimated mortality risk in both lower and higher risk groups. This may cause treatment to be delayed, increasing avoidable deaths.
The net reclassification improvement of STEMI patients using the DL (SVM selected var) produced a net reclassification improvement of 18.14%, and NSTEMI produced a net reclassification improvement of 55.80% with respect to the original TIMI risk score. Despite its low NRI value for STEMI patients, we can see that significant improvement is added to the NSTEMI population, a cohort that accounts for half or more of all ACS cases worldwide.
We have included feature selection algorithms in this study to identify factors associated with mortality in Asian ACS patients. DL (SVM selected var) predictive performance requires only 14 predictors for in-hospital mortality prediction than models developed using a conventional statistical approach. TIMI requires two distinct scores; TIMI for STEMI 8 risk factors include age, systolic blood pressure, heart rate, Killip class, anterior or left bundle infarction, prior history of angina, diabetes, or hypertension, and weight. Meanwhile, the TIMI Risk Score for patients with UA or NSTEMI is composed of seven equally weighted, binary variables [69]. Age, aspirin use during the previous seven days, coronary artery disease (CAD) risk factors, known CAD, recent anginal episodes; ST-segment alterations of at least 0.5mm on the ECG at the time of initial presentation, and elevation of serum cardiac markers [67].
DL (SVM selected var) model with best performance in this study used 14 variables that include age, heart rate, Killip Class, fasting blood sugar, and angina low-density lipoprotein, high-density lipoprotein, statin, lipid-lowering drug, chronic angina episode, ST-segment Elevation �1mm in � 2 contiguous limb leads, and coronary artery bypass grafting. The age, heart rate, Killip Class, fasting blood sugar, and angina are all shared characteristics between the TIMI risk score for STEMI and NSTEMI and the best model DL (SVM selected var). Previous studies using ML and DL algorithms identified significant predictors of mortality being age, Killip class, fasting blood glucose, heart rate, low-density lipoprotein, high-density lipoprotein, statin, ST-segment Elevation �1mm in � 2 contiguous limb leads, and coronary artery bypass grafting were used as input predictors for STEMI and ACS patients [7,38,60,70].
We also performed univariate analysis to demonstrate the association between the variables chosen by the ML algorithm and the outcomes ( Table 1). All ML feature selection models in this study selected age, heart rate, Killip class, fasting blood glucose, oral hypoglycemic drug, antiarrhythmic agent, and cardiac catheterization.
Using SHAP analysis to visualize the importance of selected variables allows us to understand and make logical inferences about how these variables were chosen as well as their impact on outcomes for the best model. According to the SHAP analysis (Fig 3), variables with higher Killip class, age, fasting blood glucose, and heart rate are all associated with a poorer outcome or non-survival. This is reported in the literature using conventional statistical methods [71,72]. Our algorithm was able to add other variables that have significant values to outcomes, such as the presence of in-patient cardiac catheterization, having an abnormal ECG on admission, and the use of oral hypoglycemics.
This finding is novel because conventional approaches have identified only advanced age and a higher Killip class as significant factors in ACS patient mortality [73]. Incorporating invasive or non-invasive management into the DL (SVM selected var) model for in-hospital mortality prediction produced noteworthy findings. Invasive intervention, such as cardiac catheterization, was associated with improved outcomes in-hospital in STEMI patients [68,74,75] TIMI and GRACE scores were generated using data collected before early reperfusion treatment and drug-eluting stents were routine. In our study, non-invasive treatment predictors associated with ACS mortality were selected included pharmacological therapy such as statin, oral hypoglycemic agents, antiarrhythmic medications, and lipid-lowering drugs. LDL-C is an independent CV risk factor, and more Asian individuals with a very high risk of recurrent cardiovascular events had LDL-C levels above the suggested range [17,19]. The TG to HDL-C ratio is also a powerful independent predictor of all-cause death and a cardiovascular risk factor [76]. Thus, intensive lipid-lowering medication is required in ACS patients [18]. Lipid-lowering therapy was common but not fully utilized throughout Asia [17]. Statins are the foundation of lipid-lowering treatment in patients with ACS [19,24].
Data imputation was performed to ensure the validity of the findings. We used two different types of imputation, MissForest and multivariable imputation using chained equations and predictive mean matching method for data imputation. MissForest is a machine learningbased method in this study [14]. The multivariable imputation using chained equations and predictive mean matching method [15] used in this study was selected as recommended in a similar study conducted on the Swedish heart registry dataset that resulted in high model performance [38].
Both data imputation methods produced a comparable predictive performance with the model built using complete cases. We initially did not include patients with more than 50% missing data because it would necessitate data imputation, which could affect our results. Because it is still a large dataset, we do not believe it is a limitation for the population. Because the dataset contained complete datasets for all follow-up time points, both the DL and TIMI calculators could be generated. Identifying factors associated with in-hospital ACS mortality prediction using complete cases, on the other hand, would result in more reliable findings. We returned to using an incomplete dataset and imputed data, and the results were similar.
Cross-validation and hyperparameter tuning improved model performance and reduced over-fitting risk [16,77]. A pair-wise corrected resampled t-test was employed to compare model predictions [56,57].
To ensure the current study's reliability, all models were validated using untouched validation data that was not used for model construction. Additionally, we demonstrated the DL model utilizing complete sets of collected variables, without a variable selection method, and found that it performed similarly to models with feature selection. This demonstrates that feature selection does not result in the loss of critical prognostic information, as Kwon et al., 2019 assert [7].
Despite a high percentage of missing values in the original dataset, we were nevertheless able to apply and compare the TIMI and DL algorithms. This is most likely because we chose a fixed endpoint of death that is unaffected by missing numbers. Another argument is that the extracted variables were adequate to improve the model's precision enough to consistently predict death.
By collecting continuous data via an electronic health record system, we were able to adapt DL and ML-based predictive algorithms to each patient's risk categorization. The study's findings also indicate that ML methods are required to rank and choose major risk factors linked with in-hospital ACS mortality. Feature selection improved model interpretation by limiting the number of predictors utilized, picking only those that are clinically relevant, and enables implementing the algorithm online as in-hospital ACS online mortality calculator. Our model chooses 14 predictors that are applicable to both STEMI and NSTEMI patients, eliminating the need for two separate algorithms such as the TIMI score. The variables are simple variables that can be obtained through routine blood tests and clinical examination. In terms of clinical application, the algorithm is deployed as a risk calculator online on the Hospital UITM intranet, which is not accessible to the public due to the study's ongoing testing, at https:// myheartacs.uitm.edu.my. We have developed the algorithm based on previous study on Asian STEMI patients https://myheartstemi.uitm.edu.my/home.php [28].
Asian patients require a population-specific, accurate, and user-friendly algorithm for better resource allocation. To the best of our knowledge, no studies on multiethnic Asian populations using predictive algorithms have been published. We are the first study to do so, and we have successfully implemented the algorithm for clinical use. Given the NCVD registry's ethnic make-up of Malay, Chinese, and Indian descendants, the study's generalizability is relevant to Asians in general. It is especially important for Malaysia, Brunei, and Singapore, as well as other Asian countries like China and India [78].
Future research will concentrate on the real-time validation of the best algorithm including several local hospitals for the continual assessment of its reliability. It is possible to improve mortality prediction by using population-specific DL models in conjunction with conventional risk score methods, which can assist clinicians in better allocate limited resources while also improving communication with patients and raising their level of awareness.

Study limitations
The purpose of this study was to evaluate the performance of a DL-based model for in-hospital mortality to that of a clinical prognostic model for 30-day mortality TIMI. Its robustness might be enhanced if factors were included and compared to other scoring systems, such as GRACE and the Heart Score. This attempt was thwarted by the absence of certain factors. We recognized that missing variables could result in a skewed outcome. We attempted to mitigate this effect by using the same population for both the TIMI and DL-based scores. It is difficult to control selection bias inside registries. We expect that subsequent investigations conducted in the actual world will corroborate our findings. Deep learning with interpretability has been researched and will be our next focus [79,80]. In contrast to medical expertise, machine learning and deep learning algorithms rely on the relationship between variables. We are concerned that the algorithm created in this study may be biased by the representativeness of the training data. As a result, we constructed and released the algorithm online, along with a repository for future results, as validation of this model in various situations is important.

Conclusion
In conclusion, we created and tested a new model for ACS risk stratification in Asian patients by incorporating machine learning feature selection with a deep-learning classification algorithm. For ACS patients, the best performing model DL (SVM selected var) predicted in-hospital mortality better than traditional risk scores and other machine-learning approaches. This study determined the viability of the proposed algorithm, which is based on a combination of machine learning and deep learning. Cardiology model that can be used in practice to make precise decisions.